The emergence of an increasing number of deadly pathogenic microorganisms that are resistant to conventional antibiotics and other antimicrobial agents has become a great concern to public health worldwide. The over-prescription/over-use of antibiotics in humans and farm animals has contributed to a rapid development of antibiotics-resistant strains of various microorganisms. For example, Staphylococcus aureus, known to be a common cause of hospital-acquired (“nosocomial”) infections that can spread to the heart, bones, lungs, and bloodstream with fatal consequences if not treated, was well controlled by penicillin in the early 1940s. However, by the late 1960s, more than 80 percent of Staphylococcus aureus had developed resistance against penicillin and, by 1972, 2 percent of Staphylococcus aureus were found to be methicillin-resistant. The percentage of methicillin-resistant bacteria continued to rise to 57.1 percent by 2002 (“Bad Bugs, No Drugs” by Infectious Diseases Society of America (“IDSA”), July 2004, based on Centers for Disease Control (“CDC”) National Nosocomial Infections Surveillance System, August 2003).
Similarly, the percentage of enterococci, an important cause of endocarditis, as well as other nosocomial infections, including urinary tract and wound infections and bacteremia, that are resistant to vancomycin (VRE) has increased since the late 1980s and, in 2002, more than 27 percent of the tested enterococci samples from intensive care units were resistant to vancomycin (by IDSA, 2004, supra). Other bacteria known to have developed antibiotics resistance include methicillin resistant, coagulase-negative staphylococci (“CNS”), ceftazidime resistant Pseudomonas aeruginosa, amipicillin resistant Escherichia coli, ceftazidime resistant Klebsiella pneumoniae, penicillin resistant Streptococcus pneumoniae, and the like. In addition, drug-resistance is no longer limited to hospital-acquired infections, but has spread to community-acquired infections, as evidenced by, for example, a total of 12,000 cases of community-acquired methicillin-resistant Staphylococcus aureus (MRSA) infections found in correctional facilities in Georgia, Calif., and Texas between 2001 and 2003 (2004, IDSA, supra).
Antibiotic-resistant microorganisms cause an enormous economic burden to society. Infectious diseases caused by drug-resistant microorganisms require longer hospitalizations, higher costs for alternative medications, more lost work days and so forth, and often result in death. According to the report by the Institute of Medicine (“IOM”) (1998, Antimicrobial Resistance: Issues and Options), infections caused by MRSA cost an average of $31,400 per case to treat. The total cost to U.S. society of drug-resistant microorganisms is said to be at least $4 billion to $5 billion annually.
Despite the urgent need for new drugs to control antimicrobial resistance, development of new antibiotics has slowed considerably in recent years as the focus of product development in the pharmaceutical fields has increasingly shifted toward chronic diseases, rather than to acute illness, such as acute bacterial infections, mainly due to higher profitability associated with the treatment of the former (March 2004, by U.S. Food and Drug Administration (“FDA”), Innovation/Stagnation: Challenge and Opportunity on the Critical Path to New Medical Products; and December 2003, by Sellers, L. J., “Big Pharma bails on anti-infectives research”, Pharmaceutical Executive 22). According to 10M and FDA, only two new classes of antibiotics have been developed in the past 30 years: oxazolidinones in 2000 and lipopeptides in 2003, and resistance to oxazolidinones have already been reported.
Gallium is a group IIIa semi-metallic element that has been used for many years for diagnosing neoplasms and inflammation in the field of nuclear medicine. Gallium has also shown some efficacy in the treatment of cancers (Adamson et al., 1975, Cancer Chemothe. Rept 59:599-610; Foster et al., 1986, Cancer Treat Rep 70:1311-1319; Chitambar et al., 1997, Am J Clin Oncol 20:173-178), symptomatic cancer-related hypercalcemia (Warrell et al., 1989, in “Gallium in the treatment of hypercalcemia and bone metastasis”, Important Advances in Oncology, pp. 205-220, J. B. Lippincott, Philadelphia; Bockman et al., 1994, Semin Arthritis Rheum 23:268-269), bone resorption (Warrell et al., 1984, J Clin Invest 73:1487-1490; Warrell et al., 1989, supra), autoimmune diseases and allograft rejection (Matkovic et al., 1991, Curr Ther Res 50:255-267; Whitacre et al., 1992, J Newuro immunol 39:175-182; Orosz C. G. et al., 1996, Transplantation 61:783-791; Lobanoff M. C. et al., 1997, Exp Eye Res 65:797-801), stimulating wound healing and tissue repair (Bockman et al., U.S. Pat. No. 5,556,645; Bockman et al., U.S. Pat. No. 6,287,606) and certain infections, such as syphilis (Levaditi C. et al., 1931, C R Hebd Seances Acad Sci Ser D Sci Nat 192:1142-1143), intracellular bacterial, fungal or parasitic infections, such as tuberculosis, histoplasmosis, and leishmaniasis, respectively (Olakanmi et al., 1997, J. Invest. Med. 45:234 A; Schlesinger et al., U.S. Pat. No. 6,203,822; Bernstein, et al., International Patent Application Publication No. WO 03/053347), Pseudomonas aeruginosa infection (Schlesinger et al., U.S. Pat. No. 6,203,822), and trypanosomiasis (Levaditi C. et al. supra).
Although the exact mechanism of gallium's activity against bone resorption and hypercalcemia is not well known, its antiproliferative properties against cancer cells and antimicrobial activities are said to be likely due to its competition with ferric iron (i.e., Fe3+) for uptake by cancer cells or microorganisms (Bernstein, 1998, Pharmacol Reviews 50(4):665-682). Iron is an essential element for most living organisms, including many pathogens, and is required for DNA synthesis and various oxidation-reduction reactions (Byers et al., 1998, Metal Ions Bio syst 35:37-66; Guerinot et al., 1994, Annu Rev Microbiol 48:743-772; Howard, 1999, Clin Micobiol Reviews 12(3):394-404). Ga3+ is known to have solution- and coordination-chemistries similar to those of Fe3+ (Shannon, 1976, Acta Crystallographica A32:751-767; Huheey et al., 1993, In Inorganic Chemistry: Principles of Structure and Reactivity I, ed. 4, Harper Collins, NY; Hancock et al., 1980, In Org Chem 19:2709-2714) and behaves very similarly to Fe3+ in vivo by binding to the iron-transport protein transferrin (Clausen et al., 1974, Cancer Res 34:1931-1937; Vallabhajosula et al., 1980, J Nucl Med 21:650-656). It is speculated that gallium enters microorganisms via their iron transport mechanisms and interferes with their DNA and protein synthesis.
U.S. Pat. No. 5,997,912 discloses a method for inhibiting growth of Pseudomonas aeruginosa by administering gallium compounds intravenously, orally or by aerosol and U.S. Patent Application Publication No. 2006/0018945 discloses a method of preventing or inhibiting biofilm growth formation using gallium compounds.
U.S. Pat. No. 6,203,822 and International Patent Application No. WO 03/053347 disclose methods for treating patients infected with intracellular bacteria, in particular, species of the genus Mycobacterium, by intravenously or orally administering gallium compounds to patients infected by this class of bacteria (also see Olakanmi et al., 2000, Infection and Immunity 68(10):5619-5627). These organisms primarily infect macrophages, which are known to store large amounts of iron and overexpress transferrin receptors. Parenterally or orally administered gallium compounds are readily taken up by macrophages through transferrin receptors and then, within these cells, are taken up by the infecting organisms, thereby interfering with the organisms' metabolism.
The antimicrobial activities of gallium against microorganisms other than intracellular organisms have thus far not been explored to a great extent.
Furthermore, the use of gallium compounds against the ever increasing number of multi-antibiotic resistant microorganisms has not been explored.